Review Article Tau-Centric Targets and Drugs in Clinical...

Review ArticleTau-Centric Targets and Drugs in Clinical Development forthe Treatment of Alzheimer’s Disease

Francesco Panza,1,2,3 Vincenzo Solfrizzi,4 Davide Seripa,3

Bruno P. Imbimbo,5 Madia Lozupone,1,6 Andrea Santamato,7 Chiara Zecca,1,2

Maria Rosaria Barulli,1,2 Antonello Bellomo,6 Alberto Pilotto,8 Antonio Daniele,9

Antonio Greco,3 and Giancarlo Logroscino1,2

1Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs,University of Bari Aldo Moro, Bari, Italy2Department of Clinical Research in Neurology, University of Bari Aldo Moro, “Pia Fondazione Cardinale G. Panico”,Tricase, Lecce, Italy3Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS “Casa Sollievo della Sofferenza”,San Giovanni Rotondo, Foggia, Italy4Geriatric Medicine-Memory Unit and Rare Disease Centre, University of Bari Aldo Moro, Bari, Italy5Research & Development Department, Chiesi Farmaceutici, Parma, Italy6Psychiatric Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy7Physical Medicine and Rehabilitation Section, “OORR” Hospital, University of Foggia, Foggia, Italy8Department of Orthogeriatrics, Rehabilitation and Stabilization, Frailty Area, E.O. Galliera NR-HS Hospital, Genova, Italy9Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy

Correspondence should be addressed to Francesco Panza; [email protected]

Received 13 October 2015; Accepted 19 May 2016

Academic Editor: Lap Ho

Copyright © 2016 Francesco Panza et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

The failure of several Phase II/III clinical trials in Alzheimer’s disease (AD) with drugs targeting 𝛽-amyloid accumulationin the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tauphosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor(TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form(MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate ADthat failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarkerstudies suggested possible benefit. The dose of 138mg/day showed potential benefits on cognitive performance of moderatelyaffected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoingPhase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, morebioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursuedbased on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.

1. Introduction

The2015 figures suggested that Alzheimer’s disease (AD)mayaffect over 5.3 million people in the USA [1]. By 2050, thenumber of new cases of AD per year is expected to grow,resulting in nearly 1 million new cases per year, and the

estimated prevalence is expected to range from 11 millionto 16 million [1]. In the last three decades, notwithstandingconsiderable advances in the AD neurobiology and medic-inal chemistry, no disease-modifying treatments have beenintroduced for this devastating and progressive neurode-generative disease [2]. The neuropathological hallmarks of

Hindawi Publishing CorporationBioMed Research InternationalVolume 2016, Article ID 3245935, 15 pageshttp://dx.doi.org/10.1155/2016/3245935

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AD are intracellular neurofibrillary tangles (NFTs) composedof paired helical filaments (PHFs) and straight filaments(SFs)mainly constituted of hyperphosphorylated tau protein,a microtubule associated protein (MAP), neuropil threads(NTs), dystrophic neurites, and extracellular deposits of 𝛽-amyloid (A𝛽) as the major component of senile plaques(SPs) in the brain. These neuropathological hallmarks ofAD strongly influenced recent therapeutic approaches, witha large portion of the many therapeutic approaches underdevelopment for AD treatment directed against the produc-tion and accumulation of A𝛽 [3]. However, several drugstargeting A𝛽 with different mechanisms of action have failedto demonstrate efficacy in randomized clinical trials ortheir development has been halted [4, 5]. For the amyloid-based approach, passive anti-A𝛽 immunization is the mostadvanced strategy for treating AD, and solanezumab, amonoclonal antibody directed at the mid-region of A𝛽,also failed but suggested some beneficial cognitive effectsin mildly affected patients [4]. A Phase III study with aplanned size of 2100 mild AD patients is ongoing to confirmthese potential benefits. Solanezumab is also being tested ina prevention study in asymptomatic older subjects, who havepositive positron emission tomography (PET) scans for brainamyloid deposits [6]. Two other monoclonal antibodies,gantenerumab, which preferentially binds to fibrillar A𝛽, andcrenezumab,which preferentially binds to soluble, oligomericand fibrillar A𝛽 deposits, are being tested in secondaryprevention trials in presymptomatic subjects with autosomaldominant AD mutations [4, 6]. These ongoing secondaryprevention trials will tell us if A𝛽 really plays a crucial rolein the pathophysiology of AD. In fact, notwithstanding thepreeminence assigned to A𝛽, one crucial point was that largenumbers of amyloid SPs can occur in the course of normalageing without any evidence of clinical dementia. Given therepeated failures of trials targeting the A𝛽 pathway in mild ormoderate AD [4], there is increasing interest in the possibilitythat tau-targeted compounds could have therapeutic utilityin AD, particularly tau aggregation inhibitors (TAIs) [5, 7,8]. The aim of this paper was to provide a comprehensivereview of tau-directed drugs for the treatment of AD, witha particular focus on TAIs and the most clinically advancedof these compounds, that is, leucomethylthioninium (LMT,leucomethylene blue (MB), LMTX�, TRx0237, TauRx Ther-apeutics Ltd., Republic of Singapore), a second-generationTAI for the AD treatment. TRx0237 shares the same activeingredient and mode of action of another first-generationTAI, that is, methylthioninium (MT, Rember�, TRx-0014,TauRx Therapeutics Ltd., Republic of Singapore), of whichis the reduced form, designed to have improved bioavail-ability and tolerability. The chloride salt of oxidized MT+ ismethylthioninium chloride (MTC or MB).

2. Pathophysiology of Tau Protein inAlzheimer’s Disease

Among pathological hallmarks of AD, the intracellular NFTscontain two aggregated tau species, hyperphosphorylatedPHFs ofMAP tau (or tau) and SFs. Tau is a 50–75 kDa proteinwith six different splice variants, referred to as 0N3R, 1N3R,

2N3R, 0N4R, 1N4R, and 2N4R [9, 10]. A short segment of tauprotein, referred to as the PHF core, from the repeat regionof the molecule is an integral structural constituent of thePHF [11]. Abnormal phosphorylation/hyperphosphorylationoccurs in tau protein in AD, beginning to pair up with otherthreads of tau into PHFs and tangle together, resulting inthe movement of tau proteins from axons to the somato-dendritic compartment of neurons, causing disintegrationof microtubules, collapse of neuron’s transport system, andformation of extremely insoluble aggregates. These changesare presumed to disrupt neuronal communication and leadto cell death [12]. NFTs are generated intracellularly, butwhen neurons die, the only NFTs remaining are “ghosttangles” which are localized outside of cells where the hostneuron has died. Ghost tangles are a common finding in ADpatients which can occur also in preclinical stages [13]. Inthis preclinical phase of AD, the earliest involved neuronsare those in the locus coeruleus, and the subcortical taulesions then reach the noradrenergic coeruleus neurons ofthe contralateral brainstem, so that the pathological pro-cess becomes symmetrical soon after its onset. Thereafter,additional nuclei with diffuse cortical projections becomeinvolved [14]. H. Braak and E. Braak demonstrated thatappearance of tau pathology in AD occurs in a characteristicpattern of development in six stages, with NFTs and NTsappearing first in the entorhinal cortex (stages I and II),followed by hippocampal (stages III and IV), and neocorticalareas (stages V and VI) [13–15]. A corresponding staging forA𝛽 deposition was compared with tau staging, with threelevels of increasing A𝛽 deposits (stages A–C), in a largeautopsy case series of subjects between the ages of 25 and95 years [16]. These findings suggested that tau aggregationprecedes A𝛽 deposits by about three decades [16], confirmingearlier reports showing the same pattern [17, 18].

The exact mechanisms by which tau protein becomesa nonfunctional entity are under debate. Tau pathology inAD is principally characterized by abnormal phosphoryla-tion/hyperphosphorylation of tau proteins, but also prote-olytic cleavage (truncation), glycosylation, nitration, acetyla-tion, O-GlcNAcylation, ubiquitination, and other abnormalposttranslational modifications are responsible for alteredtau structure in this devastating neurodegenerative disease[11, 19–25]. All these molecular events are associated with theformation of PHFs and the appearance of NFTs. In particular,abnormal phosphorylation/hyperphosphorylation, acetyla-tion, and truncation are further supported as pathologicalevents by in vitro experiments [22, 26–29], demonstrat-ing that these modifications increase fibrillization of tauand induce cell toxicity. Truncation/proteolytic cleavage oftau protein, as an alternative mechanism involving in theabnormal aggregation of tau, was proposed after extensivebiochemical analysis of the PHF core [11, 21], with prion-likeproperties in vitro. Until today, identification of the enzymethat produces this abnormal posttranslational modificationis uncertain. Caspases, which are apparently elevated in ADbrain [30, 31], are likely involved in the proteolytic processingof tau protein.The repeat domain of tau is able to catalyse andpropagate the conversion of normal soluble tau into accumu-lations of the aggregated and truncated oligomeric forms [5].

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In fact, hyperphosphorylated tau proteins bind together andform oligomeric tau, from dimers to octamers [32]. Bothhyperphosphorylated tau by itself and oligomeric tau areinvolved in synaptic loss, as observed in the wild-type humantau transgenicmouse [25, 33]. Indeed, protein aggregatesmayin general be protective in neurodegeneration by sequesteringdispersed small aggregates, oligomers, or misfolded proteins,minimizing their toxicity and eventually facilitating theirclearance by proteasomal activity or autophagy [34–36], amodel that remains to be validated with respect to tau proteinand AD [37]. However, proteolytically stable tau oligomersare able to propagate between neurons and initiate thecascade of self-propagating misfolded proteins from neuronto neuron [38, 39]. Therefore, the tau pathology of AD canbe understood as a self-propagating “prionosis,” reflectingdegrees of spread of tau that may form an endopathogenicspecies transmitting neurodegeneration from one cell to thenext throughout the brain [40]. On this basis, vaccination ofmice in experimental models of tauopathy and synucleinopa-thy, involving intracellular proteins, has showed promisingfindings [41, 42].

3. Tau-Based Drugs for the Treatment ofAlzheimer’s Disease

In AD, given the confirmed link existing between NFTtopography and clinical phenotype [43], and the abnormalposttranslational modifications of tau protein linked to thedisease [11, 19–25], therapies targeting NFTs and tau pro-tein may have potential application as drug targets againstneurodegeneration [44–46], although their development haslagged behind drugs targeting A𝛽. At present, therapiestargeting tau aim to reduce, stabilize, or prevent aggrega-tion or hyperphosphorylation of the protein [44–46]. Inparticular, several therapeutic approaches with a disease-modifying potential have been suggested: (1) inhibition of tauphosphorylation (with the inhibition of tau kinases or theactivation of tau phosphatases); (2) increase of microtubulestabilization; (3) increase of tau clearance and (4) inhibitionof tau aggregation. Some of these approaches have actuallyreached the clinic [7].

Abnormal phosphorylation of tau protein may play acritical role in the pathogenesis ofNFTdegeneration,with thebalance between kinases and phosphatases disturbed in AD,leading tau protein to become detached from microtubules,secondarily to aggregate. There is approximately a four- tofivefold higher level of total tau in AD brain compared tothat of age-matched healthy brains and this increase is all inthe form of the abnormally hyperphosphorylated tau [47]. InAD, the abnormal phosphorylation of tau could be, but notmutually exclusive, the result of upregulation of tau kinasesor downregulation of tau phosphatases [9]. In this scenario,a tau-based therapeutic approach would target a kinaseparticularly responsible for a pattern of phosphorylationcausing reduced microtubule stability.

Tau protein kinases are grouped into three main classes:proline-directed protein kinases (PDPK), protein kinasesnon-PDPK, and tyrosine protein kinases (TPK) [48]. Amongthese enzymes, the kinases with the most important role

in phosphorylation of tau protein in the brain includeglycogen synthase kinase 3𝛽 (GSK-3𝛽), cyclin-dependentkinase 5 (CDK5), cAMP-dependent protein kinase (PKA),and calcium/calmodulin-dependent kinase II (CaMKII) [49].GSK-3𝛽 may play a major role in regulating tau phospho-rylation in both physiological and pathological conditions.Interactions between GSK-3𝛽 and CDK5 also exist and willrequire further evaluation to optimize treatments aimed atthese kinases [50, 51]. Despite the challenges faced by thisapproach with respect to toxicity and specificity, a numberof efforts are underway to develop kinase inhibitors. Inparticular, in addition to a series of compounds directed atkinases of the PDPK and non-PDPK groups in preclinicaldevelopment that should be tested in in vivo studies [48, 52],one GSK-3𝛽 inhibitor, tideglusib (NP031112, NP-12, Nypta�,Zentylor�, Noscira SA,Madrid, Spain), a drugwhich belongsto the thiadiazolidinone family, was in clinical trials for ADand progressive supranuclear palsy (PSP) [5, 7, 53]. In aprevious Phase IIa trial, tideglusib was orally administeredat escalated doses of 400 up to 1000mg/day for 20 weeksto 30 patients with mild to moderate AD and the activegroup showed positive trends in four out of five clinical scalesand had significantly better response on the Mini-MentalState Examination (MMSE), with asymptomatic elevation oftransaminases, reversed with withdrawal of the drug [54].The ARGO study, a subsequent six-month, Phase IIb trial,was conducted to assess safety and efficacy of tideglusib inmild to moderate AD patients with the 15-item modifiedversion of the Alzheimer’s Disease Assessment Scale (ADAS-cog15) as the principal outcomemeasure.However, the results

demonstrated no statistically significant findings, althoughthe drug was well tolerated with diarrhea and asymptomatictransaminase elevations as the only side effects [55]. Thereare no current FDA approved trials ongoing for treatingAD with tideglusib. Activation of phosphatases, in particularprotein phosphatase 2A (PP2A), has also been proposed as apossible alternative strategy to kinase inhibition for reducingtau phosphorylation [44, 49, 56]. Multiple PP2As exist andinhibition of these phosphatases results in hyperphosphory-lation of tau, formation of NFT-like structures, and memoryimpairment in animal models [57–59]. Drugs increasing theactivity of PP2As, probably through the endogenous proteinsthat inhibit their activity, have the therapeutic potentialfor treating AD [60, 61], but no clinical trials with PP2Aactivators have been started yet.

Among tau-based anti-AD drugs, several microtubule-stabilizing agents have been tested and the studies carried outhave provided proof of concept that compoundswith the abil-ity to stabilize microtubules may have therapeutic potentialfor the treatment of AD and other neurodegenerative diseases[62], given that tau detachment from microtubules results inloss of its normal microtubule-stabilizing function, probablyleading to axonal transport impairment and eventually tosynaptic dysfunction. Some antimitotic compounds suchas paclitaxel (Taxol, Bristol-Myers Squibb Company, NewYork City, USA), epothilone D (Epo D, BMS-241027, Bristol-Myers Squibb Company, New York City, USA), or TPI-287 (Cortice Biosciences, New York City, USA, formerlyArcher Biosciences) have been used in tau transgenic animals


for their microtubule-stabilizing activity [7, 63, 64], but atpresent, these compounds did not reach the clinic due to toxicside effects (paclitaxel) or have been discontinued for AD(epothiloneD) or are in Phase I of clinical development (TPI-287) formild tomoderateAD [65] (Table 1) and primary four-repeat tauopathy, corticobasal degeneration (CBD), CBDsyndrome, and PSP [66]. In particular, in a preventativestudy, epothilone D was administered weekly for 3 monthsto young PS19 tau Tg mice that initially lacked significanttau pathology, preventing the axonal microtubule loss anddystrophy, as well as spatial learning deficits, that manifestedas these mice developed forebrain tau pathology with age[67]. In another preclinical study, in both young and oldanimals of the PS19 tauopathy model, in which tau pathologyis developing or well established, respectively, epothiloneD reversed behavioral and cognitive deficits, cleared taupathology, and increased hippocampal neuronal integrity[63]. Based on these encouraging findings, in February 2012,Bristol-Myers Squibb started a Phase I trial to evaluate thetolerability and pharmacology of epothilone D in 40 patientswithmild AD, comparing 0.003, 0.01, and 0.03mg/kg infusedonce a week for nine weeks to placebo [68]. The study endedin October 2013, but evaluation of epothilone D for AD wassubsequently discontinued.

Among microtubule-stabilizing agents, davunetide(NAPVSIPQ,NAP,AL-108, AllonTherapeutics Inc., Vancouver,Canada, Paladin Labs Inc., Montreal, Canada), an eight-amino acid peptide (with NAP representing the first threeamino acids in the peptide) derived from the activity-dependent neuroprotective protein (ADNP), has demon-strated the potential to decrease tau phosphorylation and A𝛽levels in animal models [69]. In particular, NAP stabilizesmicrotubules and reduces hyperphosphorylated tau levels[70] and in a mouse model of amyotrophic lateral sclerosis(ALS) it protected against impairments in axonal transport[71], suggesting that reduction of tau hyperphosphorylation,stabilization of microtubules, and neuroprotective effectsmay be beneficial to prevent disease progression. Anintranasal formulation of davunetide was tested in Phase IIclinical trials for both mild cognitive impairment (MCI) andPSP, given that intranasally administered NAP treatment cancross the blood-brain barrier (BBB). In 2007-2008, the PhaseII trial in 144 subjects with MCI demonstrated a statisticallysignificant improvement in memory performance comparedwith placebo at eight weeks and 16 weeks, but not 12 weeks,with well-tolerable side effects [72]. However, the resultsof the Phase II/III trial in the pure tauopathy PSP wereunimpressive [73], suggesting intervention at early stages ofthe disease [62].This result halted, for the time being, clinicaldevelopment of davunetide. This decision also prompted ahalt to recruitment into an ongoing safety and biomarkertrial, begun in 2010, of davunetide in frontotemporal lobardegeneration (FTLD) with predicted tau pathology, CBDsyndrome, or PSP [73]. An intravenous formulation ofdavunetide also exists (AL-208) and this version of the drugwas tested between 2006 and 2008 in a Phase II trial of thesafety and efficacy of a single 300 mg IV dose on cognitiveimpairment following coronary artery bypass surgery [74],with no published results.

Recent efforts to develop safe and efficacious anti-A𝛽immunotherapy usingA𝛽 peptide as an immunogen in activevaccination approaches or anti-A𝛽 antibodies for passive vac-cination may be translated to the development of a tau-basedimmunotherapy [45]. Clearance of extracellular misfoldedtau protein may prevent the transmission and spreading oftau pathology throughout the brain. Active immunizationof wild-type mice with recombinant unphosphorylated full-length human tau protein led to encephalomyelitis withneurological and behavioral deficits, axonal damage, andinflammation [75], suggesting a neurotoxic potential of tauimmunization. However, the feasibility of this approach waslater demonstrated with a 30-amino acid tau phosphopeptidespanning amino acids 379–408, including phospho-Ser atpositions 396 and 404, in two different transgenic mousemodels of disease, the JNPL3 (P301L) and htau/presenilin 1(PS1) lines [41, 76], which both resulted in a specific anti-body response, reduced tau burden, and attenuation in theseverity of behavioral and cognitive phenotypes [77]. Amongactive vaccines in clinical trials, AADvac1 (Axon peptide 108conjugated to KLH, Axon Neuroscience, Bratislava, SlovakRepublic) was the first anti-tau vaccine to enter clinicaltrials and it is a synthetic peptide derived from amino acids294 to 305 of the tau sequence, that is, KDNIKHVPGGGS,coupled to keyhole limpet hemocyanin (KLH) through anN-terminal cysteine, and administered with an Alhydrogelalum adjuvant. In transgenic tau rats, the vaccine reduced taupathology and associated behavioral deficits [78]. AADvac1was designed to target misfolded tau in AD, and its safety,tolerability, and efficacy have been evaluated in a first-in-manPhase I clinical trial conducted in three centers in Austria on30 patients with mild to moderate AD, completed on March2015 [79] (Table 1). Two withdrew due to adverse events, ofwhich one (a viral infection followed by epileptic seizure)was considered to be possibly related to the vaccine. Unfor-tunately, the double-blind, placebo-controlled portion of thestudy lasted only 12 weeks and the study evaluated only onedose of the vaccine (40 𝜇g). No data on cerebrospinal fluid(CSF) biomarkers were reported. These deficiencies limit theinterpretability of the results both in terms of safety andon target engagement. The subsequent 12-week open labelportion of the study is of limited information [80]. Patientscompleting this 24-week study had the option to enter afurther 18-month open label extension (FUNDAMANT) [81](Table 1). A separate 24-month Phase II study in 185 patientswith mild AD and a magnetic resonance imaging (MRI)consistent with this diagnosis was planned to start on March2016. This study will compare 8 subcutaneous injections of40 𝜇g of AADvac1 with the adjuvant aluminum hydroxideto placebo. The primary outcome will be safety, and sec-ondary outcomes will include cognitive and clinical batteriesas well a measure of immunogenicity. Fluorodeoxyglucose(FDG) PET, MRI volumetry, and CSF biochemistry wereset as exploratory outcomes (ClinicalTrials.gov Identifier:NCT02579252, ADAMANT) [82] (Table 1).

The vaccineACI-35 (AC ImmuneAG, Lausanne, Switzer-land and Janssen Pharmaceuticals, Beerse, Belgium) is aliposomal-based 16-amino acid tetrapalmitoylated phospho-tau peptide with specific amino acid areas incorporated into


Table 1: Ongoing phase I–III randomized controlled trials (RCTs) of tau-directed drugs in clinical development for the treatment ofAlzheimer’s disease (AD).

Compound (company)Clinicaltrials.gov identifier

Mechanism ofaction Estimated enrollment Characteristics Status

TRx0237 (LMTX)(TauRxTherapeutics Ltd.)NCT01626391

Tau aggregationinhibitor

9 patients already takingmedications for probable mildto moderate AD (2012-2013)

TRx0237 tablets 250mg/day(given as 125mg bid) for 4

weeks

Phase II trial(completed)



700 patients with probable mildAD (2012–2015)

TRx0237 100mg tabletsadministered twice daily

Phase III trial (active notrecruiting)



833 patients with probable mildto moderate AD (2013–2016)

TRx0237 125mg tabletsadministered twice daily

Phase III trial (active notrecruiting)



220 patients with behavioralvariant of FTD (2013–2016)

TRx0237 100mg tabletadministered twice daily

Phase II trial (active notrecruiting)



Subjects who have completedparticipation in a Phase II orPhase III trial with TRx0237continued access to therapy toevaluate the long-term safety of

TRx0237 (2014–2017)

All subjects will initially begiven 200mg/day of TRx0237administered twice daily.

Thereafter, dosing is flexible(100mg/day to 300mg/day)

Open label Phase II trial(currently recruiting)

TPI-287(University of California,San Francisco)NCT01966666

Microtubule-stabilizingagent

33 patients with mild tomoderate AD (2013–2015)

The purpose of the study is todetermine the highest dose of

TPI-287 that is safe andtolerable when administered as

an intravenous infusion

Phase I trial (currentlyrecruiting)

AADvac1(Axon Neuroscience SE)NCT01850238

Activetau-based

immunotherapy

30 patients with mild tomoderate AD (2013–2015)

Patients will receive 1 dose ofAADvac1 per month over 3months, for a total of 3

administrations

Phase I trial (completed)

AADvac1 (AxonNeuroscience SE)NCT02031198FUNDAMANT

Activetau-based

immunotherapy

This follow-up study continuesto observe patients who havecompleted the Phase I trial ofAADvac1, for another 18months (2014–2017)

Patients who have received 6doses in the previous trial willbe given 1-2 booster doses ofAADvac1 (2 if their antibodytiters decline below those

achieved in the previous trial).Patients who have received 3doses in the previous trial willbe given another 3 doses andthen vaccinated with booster

doses as above

18-month follow-upPhase I trial (active, not

recruiting)

AADvac1(Axon Neuroscience SE)NCT02579252 ADAMANT

Activetau-based

immunotherapy

185 patients with mild AD(2016–2019)

Patients will receive 6 doses ofAADvac1 in 4-week intervalsand then 2 individual boosterdoses in 6-month intervals, for

a total of 8 doses

Phase II trial (currentlyrecruiting)

ACI-35(AC Immune AG)

Activetau-based

immunotherapy

Patients with mild to moderateAD (2013–2014)

This Phase I trial compared twodoses of ACI-35 to investigateits safety, tolerability, and

immunogenicity

Phase I trial (active, notrecruiting)

RG7345 (RO6926496,MAb86)(Hoffmann-La Roche)NCT02281786

Passivetau-based

immunotherapy

48 healthy subjects (January2015–October 2015)

Single, ascending dose,intravenous administration

Phase I trial (active, notrecruiting)


the vaccine including phosphorylated S396 and S404 residuesthat also provides active immunization. It elicits a rapidimmune response against the immunogen in wild type andtransgenic JNPL3 (P301L) mice, resulting in a mild reductionof hyperphosphorylated pathological tau and tau pathologyby immunohistochemical characterization and increased IgGtiters and motor function of vaccinated mice [83]. ACI-35also demonstrated a good safety profile for human studies,with no adverse inflammatory response [83]. Currently, aPhase Ib trial is underway in mild to moderate AD toassess safety profile alongwith secondary outcomes includingbiomarkers, functional, and clinical change (Table 1), butdetails are not available and this trial is not listed in Clini-calTrials.gov or the World Health Organization’s clinical trialregistry.

For passive vaccination, anti-tau oligomer antibodiesmaybe ideal candidates for treating AD [84], similar to the onesdeveloped for A𝛽 [85], with exciting opportunities to validateanti-tau oligomer immunotherapeutic approaches in animalmodels. In the first program to demonstrate the efficacy oftau-based immunotherapy, this approach has been tested byinjecting anti-phospho-tau antibody PHF1, which recognizesthe pS396/pS404 epitope, intraperitoneally to JNPL3 (P301L)tau transgenic mice, with preliminary findings indicatingthat treated animals showed decreased tau pathology andfunctional impairment [86]. Similar effects were obtainedalso with other antibodies against the pS396/pS404 epitope[87, 88]. Several tau antibodies are currently in early clinicaldevelopment as therapies for AD and other tauopathies [45].Among these antibodies, RG7345 (RO6926496, MAb86, F.Hoffmann-La Roche Ltd., Basel, Switzerland) is a humanmonoclonal antibody targeting a specific tau phosphorylatedepitope at site pS422, which is prominent in neuronal den-drites [89, 90] and linked to the relocalization of tau proteinaway from microtubules and toward the somatodendriticcompartment of the neuron [89]. Furthermore, in a tripletransgenic mouse model of AD, the passive administrationof the antibody demonstrated a reduced accumulation oftau pathology with intracellular clearance of tau antibodycomplexes [90]. In January 2015, a Phase I, single-ascending-dose study in 48 healthy young men in the United Kingdomstarted, comparing the safety and pharmacokinetic measuresof six different doses to placebo, all infused intravenously [91](Table 1). Finally, BMS-986168 (IPN007, Bristol-Myers SquibbCompany, New York City, USA), although not currentlyapproved for AD but only for PSP [92], is a humanized mon-oclonal antibody directed toward extracellular, N-terminallyfragmented forms of tau (eTau), which were originally iso-lated from familial AD patient-derived pluripotent stem cells.A recent study demonstrated a correlation between eTau andA𝛽 both in vitro and in two transgenic in vivo mice models,with a reduction in A𝛽 that occurs when eTau is targeted withan antibody [93]. Secreted forms of tauwere reported to causeneuronal hyperactivity, which could, in turn, increase A𝛽production, fueling a feed-forward cycle [93]. In December2014, a Phase I, single-center, single-ascending-dose studyin 48 healthy volunteers in Texas started. This first humantrial will assess safety parameters for up to eight months afteradministration of a single infusion of BMS-986168 [94].

4. Covalent and Noncovalent TauAggregation Inhibitors for the Treatment ofAlzheimer’s Disease

Among several tau-directed approaches in AD, small molec-ular weight compounds developed to inhibit formation of tauoligomers and fibrils by blocking tau-tau aggregation havealready been tested in humans [5, 7, 95, 96]. In cell-basedand/or in vitro screening assays, several classes of agentsthat may act to prevent tau aggregation have been identified,including but not limited to polyphenols [80], porphyrins[80], phenothiazines [97], benzothiazoles/cyanines [98, 99],N-phenylamines [100], thioxothiazolidinones (rhodanines)[101], phenylthiazole-hydrazides [102], anthraquinones [103],and aminothienopyridazines (ATPZs) [104]. However, formany TAIs there is a lack of evidence of efficacy in vivofor inhibiting tau aggregation. Currently, TAIs fall into twobroad mechanistic classes, with the first class correspondingto covalent TAIs, that is, agents that either covalently modifytau directly or foster formation of covalent bonds withinor between tau proteins to yield aggregation-incompetentproducts [95]. Covalent TAIs can attack any or all speciesin an aggregation pathway but appear to be especially effi-cacious modifiers of tau monomers [95]. Among covalentTAIs, oleocanthal, a natural product aldehyde, reacts withepsilon amino groups of lysine residues [105, 106], includingresidues residing in the microtubule binding repeat region,to form imines. In addition, other natural polyphenols arecovalent TAIs, such as oleuropein aglycone [107], abundantin the extra virgin olive oil, or green tea-derived (−)-epigallocatechin gallate (EGCG) [108]. Other redox-activecompounds, including the nonneuroleptic phenothiazineMB, that is, MTC, can alsomodulate cysteine oxidation whenincubated in the absence of exogenous reducing agents [109].High concentrations of reduced sulfhydryl groups in the formof glutathione normally maintain a reducing intracellularenvironment [110], and therefore compounds acting solelythrough this mechanism could have low potency and efficacyin vivo. In general, covalent mechanisms of tau aggregationinhibition in AD are predicted to have low utility in vivo[111]. However, dimethylfumarate, an electrophile capable ofreacting covalently with cysteine sulfhydryls, was approvedfor oral treatment of multiple sclerosis [112], suggesting thatelectrophilic compounds acting through covalent inhibitorymechanisms can be useful therapeutic agents.

The second broad class of TAIs interacts with tau speciesnoncovalently, through multiple mechanisms, and with dif-ferent structures [95, 113]. Among different mechanisms,small molecules can interact directly but transiently withnatively unfolded tau protein monomer [95]. For example,curcumin has been reported to increase the reconfigurationrate (i.e., a rapid rate of interconversion between aggregationcompetent and incompetent conformations) of 𝛼-synuclein,such that occupancy of assembly competent conformationsis minimized [114]. Because tau aggregation is sensitive tocurcumin conjugates [115], this mechanism may be relevantalso for tau protein. Noncovalent TAIs also may act by block-ing formation of steric zipper structures common to cross-𝛽-sheet forming peptides. Short segments of amyloidogenic


sequences have been crystallized in forms that exhibit similarproperties as their full-length counterparts [116]. Further-more, tau filament formation can be inhibited by sequesteringtau in the form of stable off-aggregation pathway oligomers.For example, phthalocyanine tetrasulfonate, a cyclic tetrapyr-role, interacts directly with tau monomers to form SDS-stable oligomers [117]. Similarly, in a study of 𝛼-synucleinaggregation, polyphenol, phenothiazine, polyene macrolide,porphyrin, and Congo red derivatives were found to stabi-lize SDS- and Sarkosyl-insoluble oligomers [118]. SDS-stableoligomers composed of full-length tau also rapidly form atlow micromolar concentrations in the presence of cyanine,triarylmethine, rhodanine, and phenothiazine TAIs [80, 111].Since tau can coaggregate with other proteins, includingmicrotubule associated proteins and alpha-synuclein [119],TAIs may work through binding to these proteins. Indeed,numerous polyphenols have been identified that inhibitaggregation of a wide variety of amyloidogenic peptidesincluding tau and 𝛼-synuclein [113], but no studies with selec-tive TAIs are currently available to support this hypothesis.

5. Tau Aggregation Inhibitors in ClinicalDevelopment for the Treatment ofAlzheimer’s Disease: Preclinical Studiesof Methylthioninium and Derivatives

TAIs are divided into covalent and noncovalent moleculesdepending on their way to interact with tau protein. Thechemical structure of noncovalent TAIs differs significantly interms of scaffold [95]. Structure-activity relationships (SARs)were established within specific chemical series [120, 121].Like common dyes, most TAIs absorb electromagnetic radia-tion in the visible spectrum, a property linked to the propertyof delocalizing 𝜋-electron distribution [122]. Ligand polar-izability correlates with tau aggregation inhibitory potencywithin specific chemical series of cyanine, phenothiazine,arylmethine, and rhodanine derivatives [111]. MB or MTC(Rember) is and old dye repurposed as medical treatmentof tau pathologies [123]. Chemically, MTC is a tricyclicphenothiazine derivative [124] and exists in equilibriumbetween reduced (LMT) and oxidized form (MT+). Underphysiological conditions, it is present as a cation (MT+) andformulated as a chloride salt (commonly known as MB).MTC may be reduced by nicotinamide adenine dinucleotidephosphate (NADPH) or thioredoxin to give LMT (leuco-MB), an uncharged colorless compound (methylene white).MTC is excreted in the urine as a mixture of MTC, LMT,anddemethylatedmetabolites, for example, azure B and azureA [125]. MTC has been used to treat malaria [126], methe-moglobinemia [123], and depression [127]. MTC efficientlycrosses the BBB [128] and selectively penetrates neuronsafter systemic administration, particularly hippocampal cells[129]. At present, MTC and its derivatives represent the mostadvanced TAIs in clinical development for the treatmentof AD. MTC has been shown to interfere with the tau-taubinding necessary for aggregation [97]. In a cell-based modelof inducible tau aggregation, the inhibitory constant of MTCwas found to be 123 nM [5]. Other studies reported quite

different in vitro inhibitory potency (IC50) varying from

1.9 𝜇M [80] to 3.5 𝜇M [99]. The estimated trough brain con-centration of MT (Rember) and its active metabolites in thehuman brain at the 138mg/day dose was 0.18 𝜇M [130]. Thisvalue appears to be in the range of the in vitro IC

50values for

dissolution of PHFs (0.16 𝜇M) and the calculated intracellularKi for TAI activity (0.12 𝜇M) [131] but not in the range ofIC50s of other in vitro [80] and cell-based [99] studies. In tau

transgenic mouse models, MT levels in the brain followeda sigmoidal concentration-response relationship over a 10-fold range (0.13–1.38 𝜇M) after oral administration of 5–75mg/kg for 3–8 weeks [132]. Alternative mechanisms ofaction have been proposed for MT [5] including inhibitionof microtubule assembly [104] that requires IC

50of 50𝜇M

[5, 104]. However, the dose required to achieve inhibitionof microtubule assembly with MTC would be about 50 gof MTC/day [5], exceeding the median lethal dose (LD

50)

for MTC in several species. Similarly, it has been proposedthat MTCmay reduce endogenous production of tau protein[133], but EC

50for this effect is 10𝜇M, requiring a human

clinical dose of 9 g ofMTC/day, a dose that could not safely beadministered in humans. It has been also proposed thatMTCcould affect tau phosphorylation via inhibition of Hsp70ATPase [134], but again EC

50for this effect is 83𝜇M, with a

theoretical dose in humans of 75 g MTC/day.Recent in vivo and in vitro studies have suggested that

MTC may reduce tau protein aggregates in AD throughproteasomal [135] and macroautophagic [136, 137] degra-dation of the protein. Other potential effects of MTC areoxidation of cysteine sulfhydryl groups in the tau repeatdomain preventing formation of disulphide bridges to keeptau monomeric [138], acetylcholinesterase inhibition [139],nitric oxide synthase inhibition [140], noradrenaline uptakeinhibition [141], glutamatergic inhibition [142], monoamineoxidase B inhibition [143], guanylate cyclase inhibition [140],and inhibition of the aggregation of A𝛽 peptides [80, 97,144], stimulation of A𝛽 clearance [145], improvement ofbrain metabolism [146–150], improvement of astrocyte cel-lular respiration [151], improvement of brain mitochondrialamyloid-binding alcohol dehydrogenase (ABAD) functions[150], improvement of mitochondrial antioxidant properties[152, 153], improvement of the Nrf2/antioxidant responseelement (ARE) [154–156], antagonism of 𝛼7-nicotinic acetyl-choline receptors [157], inhibition of 𝛽-secretase activity[149], enhancement of mitochondrial oxidation [158], andinhibition of monoamine oxidase A [143]. However, theclinical relevance of these potential effects is doubtful. Onthe other hand, there are only a few reports on the effectof MTC on tau aggregation in vivo [135, 136, 159–161]. Inone study, MTC did not alter abnormal tau phosphorylationand failed to inhibit tau-dependent neuronal cell toxicity inzebrafish [159]. In another study, MTC treatment reduceddetergent-insoluble phosphorylated tau levels in the JNPL3(P301L) tau transgenic mice [160]. Treatment of 3-month-old rTg4510 mice for 12 weeks with oral MTC preventedbehavioral deficits and reduced soluble tau levels in thebrain [135]. JNPL3 (P301L) mice treated with MTC for 2weeks showed reduced soluble tau levels without affectinginsoluble tau levels [136]. These studies indicate that MTC


treatmentmay reduce soluble tau levels and prevent cognitivedecline when treatment begins at a time point before NFTsare present in the brain [135]. A recent study suggestedthat 6 weeks of oral treatment with MTC did not reverseestablished NFT pathology in the rTg4510 mouse model oftauopathy [161]. Some studies reported a generalized antiag-gregation effect for MTC against aggregation-prone proteins,such as prion protein [162], 𝛼-synuclein, and transactivationresponse (TAR) DNA-binding protein of Mr 43 kDa (TDP-43) [163, 164]. This further activity of MTC has potentialrelevance for the treatment of ALS and FTLD [165].

6. Clinical Efficacy and Safety ofMethylthioninium and Derivatives

Adouble-blind, randomized, placebo-controlled study evalu-ates the safety and explorative efficacy of MT (Rember) givendoses of 69mg, 138mg, and 228mg/day (equivalent to 30mg,60mg, and 100mg MTC) for 24 weeks to 321 mild to mod-erate AD patients who were not taking acetylcholinesteraseinhibitors (AChEIs) or memantine (ClinicalTrials.gov Iden-tifier: NCT00515333) (Table 1). The primary efficacy out-come of the study was the change in the ADAS-cog at24 weeks relative to baseline. The effects of treatments onregional cerebral blood flow (rCBF) decline were determinedin a subgroup of 135 patients using hexamethyl-propyl-amine-oxime single photon emission computed tomography(HMPAO-SPECT). At the end of the 24-week, double-blind,placebo-controlled treatment period, patients had the optionto enter two consecutive open label extensions of 26 and48 weeks, respectively [166]. At 24 weeks, there were notsignificant differences between treatment groups comparedto placebo in any of the efficacy variables. Post hoc subgroupanalyses revealed that in moderately affected patients therewas significant treatment benefit of the intermediate doseof 138mg/day compared to placebo on the ADAS-cog scale(5.42 points, 𝑝 = 0.047). In mildly affected patients, therewas a significant beneficial effect of the 138mg/day comparedplacebo on the all regions other than the left frontal lobe(1.97%, 𝑝 < 0.001) [166].

A total of 111 patients completed the first open labelextension of 26 weeks (ClinicalTrials.gov Identifier:NCT00684944) [167] (Table 1). At 50 weeks, themean changeof ADAS-cog score of the 138mg/day dose group was betterthan the mean change of patients initially receiving placebofor 24 weeks and then 152mg/day for 26 weeks (2.8 and 5.2points in mild and moderate patients, resp.). The most com-monly reported adverse events (incidence ≥ 5%) in MTC-treated subjects included gastrointestinal disorders (primar-ily diarrhea), renal and urinary disorders (primarily dysuriaand frequency), and falls [166]. No changes of clinical signifi-cance were observed in any routine clinical chemistry param-eters in any treatment group. Treatment with MTC produceddose-dependent decreases in red cell count and hemoglobinand increases in methemoglobin. There were 4 cases (of 307exposed to MTC) with methemoglobin greater than 3.5% (athreshold set for withdrawal of treatment) which resolvedon cessation of treatment [166]. The authors of the studyreported that the delivery of the highest dose was impaired

due to dose-dependent dissolution and absorption factorsof the 100mg MTC gelatin capsule formulation [130]. Atpresent, MTC (Rember) was discontinued for AD treatment.

7. Pharmacokinetic, Preclinical, andClinical Studies withLeucomethylthioninium and Derivatives

To the light of this functional and clinical dissociation identi-fied forMT for AD treatment, TauRxTherapeutics developedthe synthesis of a novel chemical entity, TRx0237 (LMTX), asecond-generation TAI that is a stabilized, reduced form ofMTC, in which LMT is available in an anhydrous crystallineform as the dihydromesylate or the dihydrobromide that isstable in an oxygen atmosphere [131]. X-ray crystal structuredeterminations of TRx0237 demonstrated that the nitrogenatoms at positions 3 and 7 have tetrahedral geometry [131],distinguishing it from LMT, in which the correspondingnitrogen atoms are in a trigonal pyramidal geometry and notprotonated. Synthesis of LMT has to be performed underan inert atmosphere because it rapidly oxidizes on exposureto air, while TRx0237 can be manufactured in bulk withoutthe need for deoxygenation and remains stable for at least2 years in air atmosphere. Thus, TRx0237 represents a newchemical entity that is distinct from both MTC and LMT,and it is highly soluble and exists as a single polymorph, incontrast to MTC, which is far less soluble and demonstratesheterogeneous polymorphism. TRx0237 remains stable forat least 2 years in air atmosphere, is highly soluble, andexists as a single polymorph [168]. An in vitro study showedthe ability of TRx 0237 in disrupting PHFs isolated fromAD brain tissues at the concentration at 0.16 𝜇M [131]. Thecomparative in vivo pharmacological efficacy of MTC andLMT salts (TRx0237: 5–75mg/kgwith oral administration for3–8 weeks) was assessed in these two novel transgenic taumouse lines modeling cognitive and motor endophenotypesof AD and FTLD tauopathies [169], namely, impairment inspatial learning (L1) and motor learning (L66), respectively[132]. In this in vivo study, both MTC and TRx0237 dose-dependently rescued the learning impairment and restoredbehavioral flexibility in a spatial problem-solving water mazetask in L1 (minimum effective dose: 35mgMT/kg for MTC,9mgMT/kg for TRx0237) and corrected motor learning inL66 (effective doses: 4mgMT/kg) [132]. Both compoundsreduced the number of tau-reactive neurons, particularlyin the hippocampus and entorhinal cortex in L1 and in amore widespread manner in L66. The relative superiorityof TRx0237 compared with MTC appears to be thereforemore likely due to factors related to absorption, metabolism,and distribution, rather than to inherent pharmacodynamicdifferences.

No direct information on Phase I trials is available. A4-week Phase II safety study of 250mg/day of TRx0237in 9 patients with mild to moderate AD already takingAChEIs and/or memantine began in September 2012 butwas terminated in April 2013, reportedly for administrativereasons (ClinicalTrials.gov Identifier: NCT01626391) [170](Table 1). Currently, three Phase III trials with TRx0237 are


ongoing plus an open label extension study (Table 1).The firststudy compares a single 200mg/day dose of the compoundto placebo in 700 patients with a diagnosis of either all-causedementia or AD mild enough to score above an MMSE of 20(ClinicalTrials.gov Identifier: NCT01689233) [171] (Table 1).Started in November 2012, this trial is ramping up to involvemore than 90 sites in North America and Europe, using asprimary outcome measures of efficacy the ADAS-Cog 11 andthe ADCS-CGIC scales. Temporal lobe brain metabolism ismeasured by 18F-fluorodeoxyglucose- (FDG-) PET imagingand safety parameters. The second Phase III trial compares150 and 250mg/day of TRx0237 to placebo in 833 patientswith mild to moderate AD with an MMSE of 14 or higher(ClinicalTrials.gov Identifier: NCT01689246) [172] (Table 1).Begun in 2013, this trial is being conducted at more than80 sites in North America, Australia, Europe, and Asia,using clinical (ADCS-CGIC), cognitive (ADAS-Cog 11), andsafety measures as primary outcomes. The third Phase IIItrial is evaluating TRx0237 (200mg/day) in 220 patientsaffected by the behavioral variant of frontotemporal dementia(bvFTD) and aMMSE above 20 (ClinicalTrials.gov Identifier:NCT01626378) [173] (Table 1). This trial adopted a modifiedversion of the ADCS-CGIC scale as measure of clinical effi-cacy and the revised Addenbrooke’s Cognitive Examinationas cognitive measure. This trial was started in August 2013and will involve 45 sites in North America, Europe, Australia,and Singapore. Finally, an open label extension study targetsproviding subjects who have completed participation in aPhase II or Phase III trials with TRx0237 continued access totherapy and to evaluate the long-term safety of the compoundwith an estimated study completion date of January 2017(ClinicalTrials.gov Identifier: NCT02245568) [174] (Table 1).All three Phase III trials use “active placebo” tablets thatinclude 4mg of TRx0237 as a urinary and fecal colorantto help maintain blinding; therefore, the placebo group willreceive a total of 8mg/day of TRx0237. These Phase III trialsare now fully recruited and results from these ongoing studiesinvolving 250 centers in 22 countries around the world and1,753 patients with mild to moderate AD or bvFTD areexpected in early 2016.

8. Conclusion

In the last two decades, drug discovery and developmentefforts for AD research have been dominated by the “amyloidcascade hypothesis,” focusing on targets defined by thishypothesis andproposing amyloid as themain cause of neuraldeath and dementia. Decreasing the formation or removingA𝛽 from the brain should attenuate dementia symptoms.Unfortunately, several clinical trials with anti-A𝛽 agentsfailed, challenging the hypothesis that A𝛽 accumulation isthe initiating event in the pathological AD cascade andunderscoring the need for novel therapeutic approaches andtargets. In recent years, tau-based treatments for AD havebecome a point of increasing focus and current and previousinvestigational therapies can be grouped into four categoriesincluding tau-centric active and passive immunotherapies,microtubule-stabilizing agents, tau protein kinase inhibitors,andTAIs. Among these different approaches, smallmolecular

weight compounds developed to inhibit formation of tauoligomers and fibrils by blocking tau-tau aggregation havealready reached the clinic. Among TAIs, MT belongs to aclass of diaminophenothiazines that have TAI activity invitro [97, 131]. MTC, in which MT is dosed as the oxidizedform MT+, was investigated in an exploratory Phase II dose-ranging double-blind clinical trial in 321 patients with mildto moderate AD [167]. The minimum effective dose wasidentified as 138mgMT/day at both clinical and molecularimaging endpoints at 24 weeks. Treatment at this dose wasfound to prevent the decline in regional cerebral bloodflow, particularly in medial temporal lobe structures andtemporoparietal regions.

Given that the delivery of the highest dose of MT wasimpaired due to dose-dependent dissolution and absorptionlimitations, four Phase I studies [131] and two preclinical invitro [132] and in vivo studies [133] were required to get to thebottom of the bioavailability limitations of the form of MTtested in the Phase II trial [167], setting out the basis for pro-ceeding into Phase III trials with TRx0237 for AD treatment.Therefore, clinical development of MT for AD continues,along with a new form that is more bioavailable and lesstoxic at higher doses, called TRx0237, representing a newchemical entity that is distinct from both MTC and LMT. Abroad-based approach to tau therapy appears favourable dueto the numerous pathologic mechanisms for tau pathology.The potential contribution of tau conformation to inhibitorypotency of TAIs suggests a route toward selectivity and animportant target for future structural studies. In fact, iden-tification of descriptors of inhibitory potency may provide arational approach to compound optimization [95].Therefore,the therapeutic benefit that has been reported for MT inPhase II stage and data from current Phase III trials willallow us to glean on the larger scale impact of TRx0237 andits therapeutic potential. However, the role of tau protein inAD pathogenesis should be better understood with futureresearch including investigation of themechanisms/pathwaysregulating the degradation of tau as determined by its post-translational state, studies on soluble, nonaggregated formsof tau as a primary AD agent, exploring the role of tauas an enhancer of A𝛽-induced degeneration, and clarifyingthe mechanisms by which pathological forms of tau maynegatively impact mitochondrial biology.

In this direction, the observation that acetylation ofsoluble tau has important effects on the properties oftau, including its stability and aggregation, and that tauacetylation is elevated in patients at early and moderateBraak stages of tauopathy [23] has opened new possibilitiesof tau-based pharmacological approaches. A recent studyhas proved that tau acetylated at lysine 174 is one of thetoxic species [175]. Increases in levels of this species havebeen associated with toxicity and cognitive impairment intransgenic mice. Conversely, blocking this acetylation withsalsalate, a nonsteroidal anti-inflammatory drug, preservedcognition and led to improvements in pathology. Two to threemonths of treatment preserved hippocampal volume andreduced the number of NFTs by up to two-thirds. Moreover,treated animals maintained their memories better than theiruntreated littermates [175]. Because salsalate is an approved


drug with a relatively good safety profile, it might be worthtesting in AD patients.

Competing Interests

The authors declare no conflict of interests.

Authors’ Contributions

Francesco Panza and Davide Seripa contributed equally tothis work.

Acknowledgments

This study was supported by “Ministero della Salute”, IRCCSResearch Program, Ricerca Corrente 2015–2017, Linea n.2 “Malattie Complesse e Terapie Innovative”, by the “5 ×1000” voluntary contribution and by Programmi di RicercaScientifica di Rilevante Interesse Nazionale (PRIN) 2009Grant 2009E4RM4Z.

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